Nitro and sulphamoyl substituted dibenzodiazepines

ABSTRACT

2 NITRO AND 2-DIMETHYLAMINOSULFONYL-11-(PIPERAZINYL AND 4-METHYL PIPERAZINYL)-DIBENZO(B.E)(1,4) DIAZEPINES ARE PREPARED. THEY ARE USEFUL AS C.N.S. AGENTS.

United States Patent 3,758,479 NITRO AND SULPI-IAMOYL SUBSTITUTEDDIBENZODIAZEPINES Jean Schmutz and Fritz Hunziker, Bern, Switzerland,assignors to Sandoz-Wander, Inc. No Drawing. Application Oct. 21, 1968,Ser. No. 769,373, now Patent No. 3,539,573, dated Nov. 10, 1970, whichis a continuation-in-part of abandoned application Ser. No. 712,956,Mar. 14, 1968. Divided and this application July 6, 1970, Ser. No.60,976

Claims priority, application Switzerland, Mar. 22, 1967, 4,103/67; May9, 1967, 6,557/ 67; July 14, 1967, 10,115/ 67; Nov. 3, 1967, 15,453/ 67Int. Cl. C07d 51/70 U.S. Cl. 260-268 TR 3 Claims ABSTRACT OF THEDISCLOSURE 2 nitro and 2 dimethylaminosulfonyl-ll-(piperazinyl and 4methyl piperazinyl)-dibenzo[b,e][1,4]diazepines are prepared. They areuseful as C.N.S. agents.

This is a division of then copending US. patent application Ser. No.769,373, filed Oct. 21, 1968, which issued as US. Pat. No. 3,539,573 onNov. 10, 1970, said application being in turn a continuation-in-part ofthen copending US. patent application Ser. No. 712,956, filed Mar. 14,1968, now abandoned.

The object of the present invention is to provide 11- basic-substituteddibenzo[b,e] [l,4]diazepines and dibenzo [b,f] [1,4]thiazepines usefulfor producing such pharmacologically significant action in standard testanimals as analgesic action, sedative and motility depressing action,parasympatholytic action, antihistaminic action, antitetrabenazineaction and apomorphinantagonistic action. These compounds can also beembodied in therapeutically useful forms for use as analgesics,antihistaminics, sedative and motility depressing agents,parasympatholytic agents, antiallergics, adrenolytics, neuroplegics,neuroleptics, neuroleptic antidepressants and antiemetics.

A further object of the invention is to provide ll-basic substituteddibenzo[b,e] [l,4]diazepines and dibenzo[b,f] [1,4]thiazepines havingthe above-mentioned actions of the general formula and acid additionsalts thereof. In Formula I, Z denotes bivalent sulfur, imino, or loweralkyl imino; R represents hydrogen or alkyl with l to 5 carbon atoms; Rdenotes hydrogen, alkyl with 1 to 5 carbon atoms, phenyl, R -substitutedphenyl, aminoalkyl with 1 to 5 carbon atoms, lower alkylated aminoalkylwith 2 to 8 carbon atoms, amino, or lower alkylated amino; or R and Rtogether with N form 1 pyrrolidinyl, piperidino, morpholino,thiomorpholino, l-piperazinyl, 4-(lower alkyl)-1-piperaziny1, 4- (lowerhydroxyalkyl)-l-piperazinyl and 4-(lower alkoxyloweralkyl)-l-piperazinyl; and R R and R are the same or different and denotehydrogen, halogen, hydroxy, trifluoromethyl, lower alkyl, lower alkoxyor lower alkylthio; the term lower meaning that the corresponding alkyl,alkoxy, etc., residues contain from 1 to 3 carbon atoms.

A further object of the invention is to provide ll-basic substituteddibenzo[b,e] [1,4] diazepines and dibenzo[b,f]

ice

2 [1,4]thiazepines having the above-mentioned actions of the generalformula: q Y

5 nyl of the formula -SO R in which R' represents alkyl with not morethan 3 carbon atoms.

The compounds of Formula I are obtained by treating a reaction mixturecontaining nitrilium of imonium cations of the general formulae:

wherein Y denotes bivalent sulfur, lower alkyl imino, or acyl imine, andR and R have the meaning stated above; with ammonia or an amine of theformula NHR R wherein R and R have the meaning stated above, andsubsequently splitting off a protecting acyl residue.

The starting reaction mixture containing the cations of Formula 111 is,for instance, obtained from compounds of the formula:

R4 Bl Y (IV) wherein Y, R and R have the meaning stated above, andwherein A represents halogen, lower alkoxy, lower alkylthio orp-nitrobenzylthio. The latter compounds, in turn, can be prepared bythermal cyclization of o-aminodiphenylamino-o-carboxylic acids to formlactams of the formula:

NHC0 3' rectly be'performed'using the reaction mixture which containsthe nitrilium or imonium cations of Formula III.

, The cations of Formula III can further be prepared, for example, byintramolecular Ritter reaction (reaction of the nitrile radical with aphenyl cation) from o-cyanodiphenylamines or o-cyanodiphenylsulfides, byBeckmanns rearrangement of acridone oxime or thioxanthone oxime, whichmay be suitably substituted or by Schmidt reaction of acridone orthioxanthone, which may be substituted, with hydrazoic acid. Startingwith unsymmetrically substituted oximes or ketones, Beckmannsrearrangement and the Schmidt reaction, however, yield mixtures ofisomers, which subsequently must be separated, if necessary.

The compounds of Formula I are also obtained by exposing an ureaderivative corresponding to the formula:

wherein Y, R R R and R have the meaning stated above, to dehydratingconditions, e.g. through several hours action by dehydrating agents,such as zinc dichloride, aluminium chloride, tin tetrachloride,phosphoric acid and the like, if required in the presence of an inertsolvent of suitable boiling point, such as benzene, toluene, etc., butpreferably through heating with phosphoroxychloride in toluene inaccordance with the Bischler-Napieralski reaction. Those products (I) inwhich Z is imino are obtained by this process, setting out fromcorresponding compounds wherein Y is acyl imino, by splitting ofi theacyl residue after successful ring closure.

Products of Formula I are further obtained by ring closure byintramolecular condensation of acid amides or acid thioamides having theformula:

wherein R denotes oxygen or sulfur, and Z, R R R and R have the meaningstated above. A purely thermal con densation is, in general, notpossible with the acid amides which, in turn, are obtainable, forinstance, by reduction of the corresponding nitro compounds-but ratherwith the acid thio amides, which can, for instance, be prepared bytreatment of the acid amides with phosphorus pentasulfide, and whichmust not necessarily be isolated in order to be used in the subsequentcondensation step. Especially when starting with the acid amides, thereaction will suitably be performed in the presence of condensationagents, such as phosphorus pentachloride, phosphoroxychloride, phosgene,polyphosphoric acid and so on. It is to be assumed that ring closureoccurs over intermediate compounds, such as imide chlorides, amidechlorides, imido phosphates, amido phosphates and salt-like derivativesthereof, which in general cannot be isolated. The condensation of theacid thio amides may be favored by the presence of mercury salts or byformation of intermediate imido thio ethers, which may be. activated.Heating and use of an inert diluent are indicated, and, when workingwith phosphoroxychloride and phosphorus pentachlor'ide, also addition ofcatalytic amounts of dimethylaniline or dimethylformamide.

Insofar as, by these reactions, compounds of Formula I are obtained,wherein R and/or R denote hydrogen, radicals 7R and/or R other thanhydrogen may subsequently be introduced, if desired, by reaction of theamines obtained with reactive esters of alcohols having the formulae R-OH or R OH, respectively, preferably with esters of halohydric acids,sulfuri? mid of toluene phonic acid, if desired after previous or withsimultaneous action of a basic catalyst of metallizing agent, such assodium amide, lithium amide, sodium hydride, butyl lithium, phenylsodium, sodium ethylate, or potassium tbutylate.

In the same way, a lower alkyl residue may be subsequently introduced inthe 5-position of reaction products wherein Z denotes imino, by reactingthem with a reactive ester of lower alkanols, preferably after previousor with simultaneous action of a basic catalyst or metallizing agent.

On the other hand, in order to obtain products of Formula I, wherein Zdenotes imino, a cleavable protecting residue occurring in the Y unit ofthe starting material, can be split off after ring closure in knownmanner, for instance, by subjecting a S-acetyl or S-benzoyl derivativeto selective hydrolysis, or by subjecting a 5-carbobenzoxy derivative tohydrogenolysis.

Compounds of Formula II are obtained when a compound of the formula:

wherein Z and R' have the meaning defined above and X denotes a residuecapable of being split off with the hydrogen of amines, is reacted withpiperazine or a piperazine derivative, respectively, of the formula:

wherein R' has the above-mentioned meaning.

A residue capable of being split oil with the hydrogen of amines, whichcan be bound ionically or covalently to the carbon atom, can mostconveniently be represented by halogen, sulphydryl, or alkoxy andalkylthio which may be activated, e.g., methoxy, thiomethyl orp-nitrobenzylthio, or by tosyl.

Starting materials of the Formula VIII are obtained by convertinglactams of the formula:

\Z!/ wherein Z and R have the meaning given above, into the thiolactamswhich may be followed by alkylation, or by reaction of the lactams witha halogenating agent such as phosphorus oxychloride or phosphoruspentachloride, most suitably in the presence of a catalytic amount ofdimethylaniline or dimethylformamide. Lactams of Formula X arethemselves obtained by ring closure of compounds of the formula:

wherein Z and R' have the above-mentioned meaning and R' denoteshydrogen or lower alkyl. For products wherein Z represents -S, lactamsof Formula X may also be obtained by ring closure of a compound of theformula:'

sH 1131 (XII) wherein Hal stands for halogen, or of isocyanates of theformula:

(XIII) wherein Z, R' and R' have the above-mentioned meaning and Rrepresents oxygen or sulfur. A purely thermal condensation rarelysucceeds with the acid amides but rather with the thioamides which are,for example, obtained from the acid amides by treatment with phosphoruspentasulphide and need not be isolated before the followingcondensation. Especially in the case of the acid amides it is desirableto perform the ring closure in the presence of condensing agents, suchas phosphorus pentachloride, phosphorus oxychloride, phosgene,polyphosphoric acid, and the like. It is assumed that the ring closureproceeds by way of intermediate steps such as imidochlorides,amidochlorides, imidophosphates, amidophosphates or salt-likederivatives thereof, which, in general, are not isolatable. Thecondensation of the thioamides is favoured by the presence ofmercury(II)salts or by intermediate formation of imidothioethers whichmay be activated. Heating and, if required, the use of a suitable inertsolvent are desirable, and when using phosphorus oxychloride andphosphorus pentachloride addition of catalytic amounts ofdimethylformamide or dimethylaniline.

ll-basic substituted dibenzo[b,f] [1,41thiazepines (Formula I: Z'=S-)can also be obtained by dehydration of urea derivatives of the formula:

s (XV) wherein R' has the above-mentioned meaning and R'q means R' ordenotes a removable group, especially a hydrolytically removable group.The ring closure is preferably carried out by heating in the presence ofdehydrating agents such as zinc chloride, aluminum chloride, stannicchloride, phosphoric acid, polyphosphoric acid and the like, especiallyphosphorus oxychloride or phosphorus oxychloride and phosphoruspentoxide, if desired in an inert solvent of suitable boiling point suchas benzene r toluene etc. According to the chosen reaction conditionsthe starting materials of Formula XV with a hydrolytically removablegroup R-,, e.g. carbalkoxy, especially carbethoxy, are cyclicizeddirectly to the ll-(l-piperazinyl) compounds by hydrolysis of theremovable group. Other 6 removable groups can be split off after ringclosure in a way known per se, e.g. by hydrogenolysis.

As long as R; does not denote amino, the compounds of Formula II canalso be obtained when amidines of the formula:

wherein Z has the above-mentioned meaning and R" represents R' withexclusion of amino, are treated with a reactive ester of an alcohol ofthe formula:

(XVI) HO-CHa-CH: (XVII) wherein R' has the above-mentioned meaning. Thereaction is carried out following or by simultaneous treatment with abasic catalyst or metallization agent such as sodamide, lithium amide,sodium hydride, butyl lithium, phenyl sodium, sodium ethylate orpotassium-t-butoxide. Suitable esters are those of inorganic or organicacids, e.g., hydrohalic acid, sulphonic acid or carbonic acid esters.The required amidines XVI are in turn obtained by treating compounds ofFormula VIII with ammonia.

On the other hand, compounds of Formula H, wherein R is amino, may beobtained by reduction of the corresponding nitro compounds. Thereduction is most suitably carried out by treatment with hydrogen in thepresence of a catalyst such as palladium charcoal or Raney nickel or bytreatment with stannous chloride and hydrochloric acid.

Compounds of Formula II, wherein Z denotes sulphinyl, are also obtainedby oxidation, e.g. with periodates, of the corresponding compounds inwhich Z represents sulfur.

Compounds of Formula II, wherein R represents alkylsulphinyl oralkylsulphonyl, respectively, can also be obtained by mild (e.g. withperiodates) or strong (e.g. with hydrogen peroxide or peracetic acid)oxidation of the corresponding alkylthio compounds. Products wherein R'represents alkylsulphonyl are also obtainable by strong oxidation of thecorresponding alkylsulphinyl compounds. If the oxidation is carried outon the dibenzo [b,f] [1,4]thiazepines (Z'=S) then, according to the typeof oxidizing agent used, the corresponding thiazepine sulphoxides (Z=SO)are obtained.

Finally, compounds of Formula 11, wherein R' denotes aminosulphonyl ofthe formula SO NR' R are obtained when the corresponding compoundscontaining the group -SO X instead of aminosulphonyl, wherein X denotesa residue which is removable with the hydrogen of amines, especiallyhalogen, are reacted with ammonia or an amine of the formula HNR R'wherein R';, and R' have the above defined meaning. Starting materialscontaining a sulphochloride group (-SO Cl) are obtained by diazotizationof the corresponding amino compounds followed by the Meerwein reaction.

Compounds of Formula -II, obtained according to one of these methods,wherein R' represents hydrogen can be converted to such compoundswherein R does not represent hydrogen, e.g. by treatment with reactiveesters of alcohols of the formula R' OH. Hydrohalic acid ortoluenesulphonic acid esters are suitable for this purpose. An alkylgroup R' can also be introduced by the method of reductive alkylation,i.e., by reaction with corresponding aldehydes either with hydrogen inthe presence of a catalyst or with a reducing agent such as formic acid.The introduction of a hydroxyalkyl group R' can also be carried out bytreating with a corresponding alkylene oxide.

Compounds of Formula II in which R' denotes a hydroxyalkyl group can besubsequently treated with an acylating agent to obtain products whereinR, represents an alkoyloxyalkyl group. Acid chlorides and acidanhydrides are especially suitable as acylating agents.

Subsequent introduction of a group R',, other than hydrogen, and alsosubsequent acylation of a hydroxyalkyl tion of divers amounts of activesubstance, were put with both front paws on a column of 7 cm. inaltitude, measuring the duration of persistence of the animal in thisunnatural position. The figures given in this Table II correspond to thegraphically obtained amounts of active substance, which, in the averageof 10 animals, resulted in a perseverence time of 30 seconds.

TABLE II Moving Toxicity, activity, Openfi eld LDso, EDm test, EDsoCat-alepsy, mouse, percent, percent, ED sec., s/ e s" I c-I e. Substancep.o. p.o. p.o. s.c.

2-chl0re-11-(4-methyl-1-piperazinyl)-dibenzo- [b,f][l,4]thiazepine 2700.6 0. 38 0. 72 aloperidol 125 0. 3 3. 4 0. 23 Perphenazine 120 1. 5. 00. 24 Chloropromazine 135 8. 5 4. 9 3. 8

group R, can lead to additional substitution in products in which Rdenotes an amino group; this amino group being additionally substituted.

The bases I or II obtained in this manner are in most casescrystallizable or can otherwise be distilled in high vacuum withoutdecomposition and react with inorganic and organic acids such ashydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid,phosphoric acid, acetic acid, maleic acid, succinic acid, tartaric acid,toluene sulphonic acid and the like to form addition salts which arestable in water, in which form the products may also be used.

Two bases I and II as well as their acid addition salts are newcompounds which can be used as active substances in pharmaceuticals.

The 8-ch1oro-11-(4-methyl 1 piperazinyl)-5H-dibenzo[b,c] [l,4]diazepineobtained according to Example 13 shows in animal experimentation twoproperties of a neuroplegic with intense analgesic, sedative,parasympatholytic and sympatholytic action. The analgesic action isdetermined by measuring the pain threshold during electrical stimulationof the dental pulp in the rabbit. It is compared in Table I below withthe action of known analgesics.

The sedative and motility depressing effect may be seen from the movingactivity test according to Caviezel and Baillod [Pharm. Acta Helv. 33,469 (1968)] in the mouse. In this test, the ED 50% in mg./ kg. p.o.amounts to 2.5. Comparative figures will be seen in Table 11 below.

The 2-chloro-11-(4-rnethyl 1 piperazinyl)-dibenzo [b,f][1,4]thiazepineobtained according to Example 14 shows in animal experimentation, theproperties of a neuroleptic agent with intense motility depressingaction and antagonistic effect to apomorphine. The motility depressingaction was determined by measuring the moving activity in the mouse inaccordance with the method of Caviezel and Baillod [Pharm. Acta Helv.33, 469 (1958)], as well as by the open-field test in the rat accordingto the method of Janssen et a1. [Psychopharmacologia 1, 389 (1960)],using animals in each test. In Table II below, the average valuesobtained are compared with the corresponding data of known neuroleptics.Furthermore, Table II shows comparative data for the acute toxicity inthe mouse as well as for cataleptic action. The latter was tested inrats, which, in several intervals after 5.6. injec- Compounds of FormulaII in which R denotes nitro show also the typical behaviour pattern forneuroleptics. As mentioned above, this manifests pharmacologically,e.g., in a suppression of locomotor activity, a cataleptic and/or anapomorphine antagonising effect in mice or rats, respectively. The mosteffective compounds in this respect are2-nitro-1l-(4rnethyl-l-piperazinyD-dibenzo- I [b,f][1,4]thiazepine,obtained according to Example 95,

as well as a comparatively weak cataleptic and locomotor.

activity suppressing efiiect.

Pronounced antiemetic activity is shown by Z-dimethylaminosulphonyl 11(4-methyl-1-piperazinyl)-dibenzo- [b,f] [1,4]thiazepine and2-methylsulphonyl-1l-(4-methyl 1 piperazinyl)-dibenzo[b,f][1,4]thiazepine obtained according to Examples 96 or 105, respectively,and their acid addition salts.

To further illustrate the pharmacological activity and the dosage levelsin which the compounds of the present invention are used to provide anindicated pharmacological analgesic activity, the following data aregiven in Table III:

TABLE III Toxicity (mouse), Threshold LD Dose, current (in mg.lkg.,mg./kg., percent of the i.v. i.v. control values) Proguct of ExampleNo.:

Table IV gives data on compounds which exhibit sedative and motilitydepressing action, as determined in accordance with the details statedin columns 8 and 9.

TABLE IV Toxicity (mouse), LD msxmg./kg., p.o.

Product of Egample No.:

Table V gives data on compounds which exhibit parasympatholytic action.This action is determined by the property of such substances to reduceor annul the hypotensive action which is otherwise observed in thenarcotized cat upon electric stimulation of the Vagus nerve or uponadministration of acetylcholine (ACH). In Table V those doses ofinventive products are shown which cause 75% reduction of thehypotensive action of Vagus stimulation and ACH, respectively:

TABLE V Toxicity Parasympatholytic action,

Vagus stimulation Upon ACH Parasympatholytic product of2Examp1 No TableVI gives data on compounds which exhibit antihistaminic action. Theantihistaminic action is determined by the standard histamineasthma-test in the guinea pig. Upon p.o. administration of the testcompound, the animals are put in an atmosphere containing histamineaerosol. In the following Table VI those doses of inventive products areshown which protect 50% of the animals completely against histamineasthma during at least 10 minutes (ED 50):

The compounds of this invention can be administered in the form ofpharmaceutical preparations containing, besides the active substance,organic or inorganic solid or liquid carriers suitable for enteral orparenteral ad ministration. The pharmaceutical preparations may be, forexample, in the form of tablets, dragees, or solutions for injection.

EXAMPLE 1 A 10.0 g. quantity of5-methyl-7-methylthio-10,1l-dihydro-ll-oxo-5H-dibenzo[b,e][1,4]diazepineis heated under reflux conditions during 1 hour with 10 g. of phosphoruspentachloride in 350 ml. of dry chloroform. The yellow-red solution isconcentrated to dryness in vacuo. The residue is heated under reflux for3 hours with 38 ml. of N-methylpiperazine in 160 ml. of absolutedioxane. Upon concentration in vacuo of the dioxane solution as far aspossible, the residue is distributed between diluted soda lye andbenzene. The biphasic solution is separated from undissolved substanceby filtration. After Washing of the benzenic phase with water, thealkaline material is extracted by shaking with diluted acetic acid,freed by addition of ammonia and dissolved in benzene. The benzenicphase is washed with water, dried over sodium sulfate and concentrated.After clarifying with alumina, the residual solvent is evaporated. Theresidue crystallizes spontaneously from ether and, afterrecrystallization from acetone/petroleum ether, yields 6.9 g. (52% ofthe theoretical amount) of5-methyl-7-methylthio-1l-(4-methyll-piperazinyl)-5H-dibenzo(b,e][1,41diazepine in the form of yellow prisms, having a melting point ofl71l73 C.

EXAMPLE 2 8.4 g. of 3-methyl-10,11-dihydro-11-oxo-dibenzo[b,f][l,4]thiazepine are heated for 2 hours under reflux with 9 g. ofphosphorus pentachloride in ml. of dry chloroform. Upon evaporation todryness in vacuo, 30 ml. of N-methylpiperazine are slowly added; thenheating under reflux is continued for further 3 hours. The reactionmixture is worked up as in Example 1, with the exception that ether isused in place of benzene in the extraction step. The3-methyl-11-(4-methyl-1-piperazinyl)- dibenzo[b,f][1,4]thiazepinedistills at 178 C./0.02 mm. Hg and can be crystallized from ether/petroleum ether. The yield is 6.9 g. (61% of the theoretical) of faintyellow prisms having a melting point of 92-95 C.

EXAMPLE 3 A solution of 9.6 g. of5-methyl-8-chloro-l0,1l-dihydro-l1-oxo-5H-dibenzo[b,e][1,4]diazepine in75 ml. of phosphoroxychloride, containing 3 ml. of dimethylaniline, isheated for 2 hours under reflux. The dry residue obtained uponevaporation of the reaction mixture in vacuo, is mixed with 50 ml. ofN-methylpiperazine in 40 ml. of dioxane and heated under reflux for 4hours. Working up of the reaction mixture as in Example 2 yields 8.1 g.(66% of the theoretical amount) of 5-methyl-8-chlorol1-(4-methyl 1piperazinyl)-5H-dibenzo[b,e][1,41diazepine in the form of reddish-yellowplates of melting point 164-165 C. (from ether/petroleum ether).

EXAMPLE 4 11.8 g. of 10,1l-dihydro-l1-oxo-5H-dibenzo[b,e][1,4]diazepine, 0.4 ml. of dimethylformamide and 8.6 g. ofphosphoroxychloride in 120 ml. of dry chloroform are agitated during 2hours under reflux conditions. Upon concentration of the reactionmixture to dryness in vacuo, the residue is heated under reflux for 4hours with 30 ml. .of absolute dioxane and 30 ml. of piperidine. Thereaction mixture is worked up in thesame manner as in Example 2, withthe exception that diluted hydrochloric acid is used in place of aceticacid for isolating the base. 6.1 g. (39% of the theoretical yield) ofIl-piperidino- 5H-dibenzo[b,e][1,4]diazepine are obtained in the form ofyellow plates of melting point 129-131 C. (from ether/ petroleum ether).

1 1 EXAMPLE The reaction mixture obtained from 0.7 g. of potassium and15 ml. of tertiary butanol is mixed with 4.4 g. of 7-chloro-11 mercapto5H dibenzo[b,e] [1,4] diazepine in 50 ml. of dioxane and heated for 1hour under reflux. Upon cooling, a solution of 3.5 g. ofn-nitrobenzylchloride in ml. of dioxanc is added drop by drop withagitation, and the mixture is again refluxed during 2 hours and thenconcentrated to dryness in vacuo. The residue is distributed betweenwater and chloroform. The chloroformic solution is washed with dilutedsoda lye and water, dried over sodium sulfate and concentrated. Uponaddition of petroleum ether,7-chloro-1l-p-nitrobenzylmercapto-5H-dibenzo[b,e] [l,4]diazepinecrystallizes in an amount corresponding to 79% of the theoretical yield.After recrystallization from acetone/petroleum ether the product has amelting point of 178-182 C.

A solution of 4.6 g. of this product in 10 ml. of N-methyl-piperazine,containing 3 drops of glacial acetic acid, is heated during 24 hoursunder reflux. The reaction mixture is concentrated to dryness in vacuo.The residue is distributed between ether and ammonia/water. The etherealsolution is washed with water and extracted with l-n. acetic acid. Theacid extract is clarified with charcoal, mixed with concentrated ammoniasolution and saturated with sodium chloride. The alkaline precipitate isseparated by filtration and recrystallized from acetone/ petroleumether. 3.2 g. (85% of the theoretical yield) of 7-chloro 11(4-methyl-l-piperazinyl)-5H-dibenzo- [b,e] [1,4]diazepine are obtained,having a melting point of 179-181 C.

EXAMPLE 6 A 7.05 g. quantity of N-methyl-o-ureido-diphenylamine isboiled under reflux conditions for 3 hours with ml. ofphosphoroxychloride in 140 ml. of absolute toluene, whereupon ayellowish-red, syrupy product separates out. After evaporating thesolvent, the residue is decomposed with diluted ammonia solution, theorganic substance which forms as a viscous oil is dissolved inchloroform, and the chloroform extract is washed with water, dried oversodium sulfate and evaporated. As residue, there are obtained 6.58 gm.of a yellow resinous product which solidifies with foam in vacuum andmost of which on distribution between ether and diluted hydrochloricacid passes into the acid layer. From the hydrochloric acid extract, thebase is liberated with ammonia, separated by suction and washed withwater. After drying, the product is recrystallized from acetone/petroleum ether to provide a yield of 4.2 gm. (61% of the theoretical)of yellow 5 methyl 11 amino 5H dibenzo [b,e][l,4]diazepine having amelting point 167l68 C.

The N-methyl-o-ureido-diphenylamine used as the starting material can beobtained in the form of needles having a melting point of l80-l83 C., ina yield of 90%, by introducing, while cooling, potassium cyanate inslight excess into an acetic solution of N-methyl-o-amino-diphenylamineand by aspirating the precipitate which forms after diluting with waterand allowing the whole to stand, by washing with diluted hydrochloricacid and water and by recrystallizing from acetone/water.

Identical products as in Example 6 are obtained, in some cases howeverin poor yields, by using phosphoric acid, aluminium chloride or zincchloride as condensing agents.

EXAMPLE 7 By proceeding in the same way as in Example 6, but usingo-piperidylamido-diphenylisulfide as the starting material and leavingout the toluene solvent, there is obtained1l-piperidine-dibenzo[b,f][1,4]thiazepine, melting point 133-134 C., ina yield of 12% of the theoretical.

1 2 EXAMPLE 8 A 3.5 g. quantity of 1l-chloro-dibenzo[b,f][1,4]thiazepineis dissolved in 40 ml. of absolute xylol, mixed with 4.3 gm. ofpiperidine and heated for 5 hours under reflux conditions. The reactionmixture is diluted with water and made alkaline with concentrated sodiumhydroxide solution. The xylol layer is separated, washed until neutralwith water and extracted with hydrochloric acid. The acid extracts aremade alkaline with concentrated ammonia solution and the precipitatedoil extracted with ether. The ethereal solution is washed with water andevaporated. The residue is crystallized from ether/petroleum ether. Ayield of 3.4 gm. of ll-piperidino-dibenzo- [b,f] [1,4]thiazepine isobtained having a melting point of 133-134 C., which is identical withthe product of Example 7.

EXAMPLE 9 By proceeding as in Example 8 but setting out from imido thioether and N-methyl-piperazine and using a trace of glacial acetic acidas the catalyst, there is obtained ll(4-methyl-l-piperazinyl)-5H-dibenzo[b,f] [1,4] diazepine having a metingpoint of 184-l85 C. (from acetone/petroleum ether) in a yield of 87% ofthe theoretical.

EXAMPLE 10 A mixture of 6.2 g. of N methyl 2aminodiphenylamine-2'-carboxylic acid piperidide, 6.0 g. ofphosphoruspentasulfide and 60 ml. of pyridine is heated during 4 hours underreflux. The reaction mixture is evaporated to dryness in vacuo. ml. of2-n. aqueous soda solution are added to the residue, and after a certaintime the yellow crystalline precipitate is taken into benzene. Thebenzenic solution is extracted with 2-n. hydrochloric acid. The acidextract is clarified with charcoal and treated with concentrated ammoniawater to precipitate the alkaline substance, which is dissolved inether. The ethereal solution is washed with water and dried over sodiumsulfate. The residue obtained yields, after recrystallization fromether/petroleum ether, 3.4 g. (57% of the theoretical amount) ofS-methyl-ll-piperidine-SH-dibenzo[b,e] [1,4] diazepine in the form oflemon-colored grains having a melting point of 162-163 C.

EXAMPLE 1 1 6.2 g. of N methyl 2 aminodiphenylamine-2'-carboxylic acid(fl-dimethylamino)ethylamide and 6 g. of phosphorus pentasulfide in 60ml. of pyridine are heated during 4 hours under reflux. The reactionmixture is worked up as in Example 10, however, the extraction isperformed using diluted acetic acid in place of hydrochloric acid. 3.5g. (59% of the theoretical yield) of 5- methyl 11 (B dimethylaminoethylamino)-SH-dibenzo[b,e][1,4]diazepine are obtained in the form ofyellow plates having a melting point of 167170 C. (from acetone/petroleum ether).

EXAMPLE 12 6.0 g. of Z-aminodiphenylamine 2' carboxylic acid(ti-dimethylamino)ethylamide are triturated during 1 /2 hours with 60 g.of polyphosphoric acid (average degree of polymerization=3.4) at 150 C.Ice and concentrated aqueous ammonia solution are added to thehomogeneous syrupy reaction mixture until it is alkaline. Theprecipitate is dissolved in ether. Extraction of the base and furtherpurification are performed as in Example 11. 2.0 g. (35% of thetheoretical yield) of ll-(fi-dimethylaminoethylamino) 5Hdibenzo[b,e][1,4]diazepine are obtained in the form of light yellowgrains having a melting point of 143144 C. (from ether/petroleum ether).

EXAMPLE 13 7.4 g. of 2-amino-4-chlorodiphenylamine-Z'-carboxylic acid(4"-methyl)piperazide and 35 ml. of phosphoroxychloride are heated for 3hours under reflux in the presence of 1.4 ml. of N,N-dimethylaniline.Upon concentration of the reaction mixture in vacuo as far as possible,the residue is distributed between benzene and ammonia/ ice water. Theseparation and purification of the basic component is performed as inExample 11. 2.9 g. (41% of the theoretical yield) of8-chl0ro-11-(4-methyl-1-piperazinyl)-H-dibenzo[b,e,] [l,4]diazepine areobtained in the form of yellow grains of melting point 182-184 C. (fromacetone/ petroleum ether).

EXAMPLE 14 6.8 g. of 2amino-4'chlorodiphenylsulfide-2'-carboxylic acid(4"-methyl)piperazide are heated for 1 hour under reflux with 7 g. ofphosphorus pentachloride in 35 m1. of

phosphoroxychloride, in the presence of 10 drops of dimethylformamide.The residue obtained by evaporation of the reaction mixture in vacuo isworked up as in Example 12r 2] g. (42% of the theoretical yield) of 2-chloro l1 (4 methyl 1 piperazinyl)-dibenzo[b,f] [1,4]thiazepine areobtained in the form of faint yellow grains of melting point 118-120 C.(from ether/petroleum ether).

In like manner as in Examples 1 to 14, there are obtained from thecorresponding starting materials the products listed in the followingTable VII. Therein R R R R and Z denote the corresponding residues ofFormula I. In the last column, e means ether, pe" petroleum ether, andac acetone.

TABLE VII .P.or 13.1. ofthe base, Example Z R3 or R4 R2 C.

15 l |l H N(C2 s)2 16 N H N/ \6 201-203 (from ae/pe).

17 III E NH-CH':CHr-N(CZH5)2 205-210 (0.01 mm. Hg).

18 T| I- H NHCH2CH2CH2N(CH3)2 148-150 (from e/pe).

10. 471- H NH-(\3H(CH) 3' N(CH3) 2 *204-208 (0.05 mm. Hg).

H C H3 20 N- H 182-184 (from ae/pe).

\ N N--CH2CH2OH H 21 -III- H NH'CH2CH2CHz-N(CHs)2 73-75 (from e/pe) 22.N- H 124-125 (from e/pe).

| N N- CH3 C Ha 23 -1TI 2-OCH: NH-CHz-CH2N(CH3)z 24 N 2-0 CH3 l -N N-CH3 H 25 I*|I B-OCHa NHCH2CHz-N(CH3)2 26 IET- 7-Cl NHCH2CH2-N (CH3)2155-156 (from e/pe).

27 N- 7-C1 201-203 (from ac/H20).

l N N-CHa CH3 28 lf- 8-01 N/ 148-151 (from e/pe).

29 IIP- S-Cl NHCH2CH2N (C1192 156-158 (from e/pe).

30 IIT- H NH-(EH- (CH2) a-N (C2H5) 2 a H CH3 3 IT- 7-C1 N/ 158-159 (frome/pe).

32 I |I 7-Cl -NH-CHz-CHN (C1192 157-159 (from ac/HzO).

33 N 8-0 CH3 139 (from ae/pe).

| N N-CHa CH:

See footnotes at end of table.

TABLE VII- Continued R1 .:V V V.. 3 N M.P. or *B.P. ofthcbaso,

Example Z R; or R4 .Rg' C. i

92 s H r VA. 158 i60:(trom oc/pe). v

men-@oom 93 n -s H 4 N N'CH2-OH:OH...

94 -s- H t").

1 The hydrochloride decomposes at 230240 C.

i A hygroscopic d-tartrate (1:1 mole) was obtained.

a A hygroscopic d-tartrate (1:1) mole was obtained.

4 The hygroscopic dihydroehloride melts at temperaturesabove 160 C 5 Thehygroscopic dihydrochloride-diligdrate decomposesflrom methanol/ether)at 210"v C:

A hygroscopic dihydroehloride was tained.

7 The dihydrochloride melts, while decomposing, at 244-246" C. (fromisopropanol/ether).

The hydrochloride melts at 190213 C. (from methanol/ether).

The dihydrochloride melts, while decomposing, at 192 C. (fromisopropanol/ether).

The hydrochloride decomposes above 215 0.

The hydrochloride melts at 194-200 C. (from methanol/ether). Thehydrochloride melts at 196197 C. (from ethanol/ether).

13 The dihydrochloride melts at 215225 C. ,(from methanol/ether). 14 Thehydrochloride melts at 230-248" C. (from methanol/ether). Thehydrochloride melts at 179-180 C. (from methanol/ether).

2.0 g. of 2 nitro-10,l1-dihydro-11-oxo-dibenzo[b,f] [l,4]-thiazepine(M.P. 270286 C. dec.) and 1 ml. of N, N-dimethylaniline are refluxedwith 15 ml. of'phosphorus oxychloride for 5 hours after which thereaction mixture is evaporated to dryness in vacuo. The residueis'treated with xylene, once again evaporated in vacuo and then refluxedfor 16 hours with 15 ml. of N-methylpiperazine and 10 ml. of dioxane.After evaporating to dryness in vacuo the residue is distributed betweenether and dilute aqueous ammonia solution. The ether phase is washedtwice with water and then shaken out with dilute acetic acid. The baseis set free from the acid extracts by addition of concentrated ammoniasolution and taken upin ether. The ether phase is Washed four times withwater, dried over sodium sulphate and evaporated. The resinous residueobtained is then dissolved in ether, filtered through aluminium oxideand evaporated. The residue is crystallized from acetone/petroleum etherto give 1.7 g. of 2-nitro-11- (4 methyl-l-piperazinyl)-dibenzo[b,f][l,4]thiazepine in the form of yellow matted needles of melting point141- 142 C.

EXAMPLE 96 4.5 g. of 2dimethylaminosulphonyl-10,1l-dihydro-lloxodibenzo[b,f][1,4]thiazepine(M.P. 283284 C.) and 1.3 ml. of N,N-dimethylaniline are refluxed in 40ml. of phosphorus oxychloride for 4.5 hours. The excess phosphorusoxychloride is then distilled off in vacuo and the residue is dissolvedin xylene. The xylene solution is poured onto ice/water, shaken outtwice with dilute hydrochloric acid and once with water, dried oversodium sulphate and then concentrated to 100 ml. in vacuo. 8 ml. of Nrneth ylpiperazine are added and the reaction mixture is refluxed for 4hours and then treated with dilute soda lye and Water. The xylene phaseis separated and shaken out with dilute hydrochloric acid. The acidextracts are made alkaline with concentrated ammonia solution and thebase which separates is extracted with chloroform. After drying oversodium sulphate the chloroform extracts are evaporated in vacuo. Theresidue is crystallized from acetone/petroleum ether whereby 4.9 g. ofZ-dimethylaminosulphonyl-11-(4-methyl 1 piperazinyl) dibenzo[b,f][1,4]thiazepine are obtained in the form of slightly yellow needles ofmelting point 192-193 C.

EXAMPLE 97 3.72 g. of 2amino-2'-(4-methyl-1"-piperazinyl-carbonyl)-4'-nitro-diphenylsulphide(M.P. 184-187 C.) and 1 ml. of N,N-dimethylaniline are refluxed for 3hours in 20 ml. of phosphorus oxychloride after which the reactionmixture isevaporated to dryness. The residue'is treated with xylene,once again evaporated and then partitioned between benzene, and dilutehydrochloric acid. The base is set free from the acid extracts withconcentrated ammonia solution and taken up in benzene. The benzenesolution is exhaustively extracted with dilute acetic acid and theacetic acid extracts are treated with active charcoal. The basicfraction is set free, under ice-cooling, with concentrated ammoniasolution and taken up in chloroform. The chloroform extracts are washedwith water, dried over sodium sulphate and evaporated. The residue isdissolved in ether and filtered through aluminium oxide. The residueobtained after evaporation of the solvent'is systematically crystallizedfrom acetone/ether/ petroleum ether. The first fraction to crystallizeis 0.6 g. of starting material. 07 2- g. of 2-nitro-1'1"-(4-methyl-'1-piperazinyl)-dibenzo [b.f] [1,4]thiazepine of melting point 138-141 C.are obtained from the more soluble portion. This compound is identicalto the product obtained according to Examp1e9'5." v a EXAMPLE 98 11.5 g.of .l-nitroel1- (4rmethyl-l-piperazinyl)-dibenzo [b,f][l,4]thiazepineobtained according to Example are mixed with 24.5 g. pf stann0uschloride and while stirring and cooling with ice, treat ed dropwise withdilute hydrochloric acid (238 ml. of concetrated hydrochloric acid and100 ml. of water). The reaction mixture becomes lighter in colour and awhite precipitate is formed; After the addition is complete the reactionmixture is stirred for a further 20 minutes while cooling, then for 15minutes at 40 C. The reaction mixture is thereupon made stronglyalkalinewith concentrated soda lye and the precipitate taken up inether. The ether phase is exhaustively shaken out with dilute aceticacid and the base liberated from the acetic extracts by addition ofconcentrated am monia solution and taken up in ether. The ether phase iswashed with water, dried over sodium sulphate and evaporated. Theresidue is dissolved in ether, filtered through aluminium oxideandevaporated. After crystallization of the residue from ether/petroleumether 10.05 g. of 2 amino-11-(4-methyl-l-piperazinyl)-dibenzo[b,f][1,4]thiazepine are obtained as colourless prisms of melting point16750,

A solution'of 3.4 g. of sodium metaperiodate in 40 ml. of water is addedin one lot to a solution of 5.3 g. of 2- nitro-11-(4-methyl 1-"piperazinyl)-dibenzo[b.fl[1 4] thiazepine, obtained according toExample 95, while stirring under ice-cooling. The reaction mixture isthen stirred at room temperature for 5 hours and left to standovernight. After diluting with water and treating with active charcoalthe basic fraction is set free under ice-cool- 22 By analogousprocedures as in Examples 95-97 e.g., the products given in thefollowing Table VIII are obtained. In the table Z, R, and R: have theabove defined meaning. In the column on the right hand side ac meansacetone, e=ether, ch=chloroform, me=methanol 5 mg wlth concentrated sodalye and taken up m benzene. and pe=petroleum ether.

TABLE VIII Example Z R; R; Melting point, C.

H -Na Base: 153-155 (from art/D CH2-CH2-OH N0: Base: 130-134 (fromac/pe).

H SO;NCH;)2 Base: 186-188 (from ch/e).

C a -SOzN CH Base: 193-195 (from ac/pe).

CH; -SO CH; Base: 219-223 (from ec/pe).

H -S0 CH; Base: 180-183 (from ch/pe).

-GH; -SOzCzHr Base: 169-110 (from ch/pe).

H -SO;C H; Maleate: 180-185 (from melee/e).

N0a Base: 110-112 (from 230/1 S0:N(CH;) Base: 147-150 (irom arc/D SOzCHDihydrobromide: 225-230 (dec.;

h-ozn me/ethyl acetate). SOzCH; Dihydrobromlde: 233-248 (from me/ethylacetate).

S01NHCH; Base: 218-222 (from ac/pe). --SO2NHCH; Base: 168-170 (fromac/pe). NO2 Base: 174-176 (from ac/pe).

The benzene solution is washed with water, dried over sodium sulphateand concentrated. The solution is filtered through aluminium oxide andevaporated to dryness. The residue is crystallized from acetone andacetone/petroleum ether to give 4.3 g. of2-nitro-11-(4-methyl-1-piperazinyl)-dibenzo[b,f] [1,4]thizaepine-5-oxidein the form of yellow matted needles of melting point 182-185 C.

EXAMPLE 100 A solution of 3.42 g. of sodium metaperiodate in ml. ofwater is given in 3 portions to a stirred solution of 6.24 ofZ-dimethylaminosulphonyl-1l-(4-methyl-1-piperazinyl)-dibenzo[b,f][l,4]thiazepine obtained according to Example 96, in 40 ml. of water and10 ml. of glacial acetic acid at 0 C. A precipitate which appears isbrought into solution by adding ml. of 2 N acetic acid. The reactionmixture is kept at room temperature for 24 hours, then made alkalinewith concentrated soda lye and shaken out with chloroform. Thechloroform extracts are washed with water, dried over sodium sulphateand evaporated to dryness in vacuo. The residue is crystallized fromacetone/petroleum ether to give 5.9 g. of Z-dimethylaminosulphonyl 11 (4methyl-1-piperazinyl)-dibenzo[b,f] 45 [1,4]thiazepine-5-oxide of meltingpoint 208-2l0 C.

References Cited UNITED STATES PATENTS 3,084,160 4/ 1963 Jacob 260268 X3,268,557 8/ 1966 Weber 260268 3,458,516 7/1969 Howell et al. 2602683,462,436 8/1969 Fouche 260268 3,546,226 12/ 1970 Schmutz et a1. 260268OTHER REFERENCES Chem. Abstr., vol. 70, col. 96835V (1969), AbstractingS. African, 6001, 370.

DONALD G. DAUS, Primary Examiner

